A major conceptual advance for innate immunity has been the discovery of Pathogen-associated Molecular Pattern recognition receptors or sensors, a prime example being the toll-like receptor (TLR). More recently, we and others discovered a large family of pathogen sensors in humans and mice, called the NLR (nucleotide-binding domain, leucine-rich repeat containing) family, known previously as CATERPILLER, NACHT-LRR, or NOD-like receptor. An important function of NLR proteins is the formation of a biochemically-defined complex, called the inflammasome, which processes pro-caspase-1 and pro-IL-1b/IL- 18 to their mature forms. In addition to this role, some NLRs have a profound effect on T cell responses. This creates a new paradigm where NLRs can also influence adaptive immunity. Additional studies indicate that NLR proteins mediate type I interferon (IFN) production in response to viruses through an interference of the intracellular pathway mediated by the mitochondria! anti-viral signaling molecule (MAVS, a.k.a. IPS, VISA and CARDIF). This proposal will examine the divergent roles of NLR during flavivirus infection. Flaviviruses such as Dengue (DENV) and West Nile (WNV) have surfaced at the forefront of biodefense and emerging infections. Type I IFN is pivotal in anti-flaviviral host defense, and the intracellular pathway of viral RNA recognition is crucial for this response during DENV and WNV viral infection. Of equal importance, IL-1 Droduction has been observed by several groups as being a crucial outcome of human infection by Flaviviruses. Finally, adaptive immunity is unquestionably of importance to anti-flaviviral host response. However, the link between NLR members to any of these anti-viral host responses has not been explored. In this proposal, we plan to explore the roles of different NLRs in eliciting interferon response, inflammasome :unction, and adaptive immunity upon infection by WNV and DENV.